Description of Applicant's goals and Environment My long term goal is to become an independent investigator and to study neuronal mechanisms of addiction and related neuropathies. I had a postdoctoral experience in which I worked on mice with mutations on nicotinic receptors (nAChR), using behavior, in vivo pharmacology, microdialysis, etc. My current goal is to verify that the conclusions of my mouse research are applicable to humans. I will study whether certain nicotinic receptors in specific brain areas are critical for nicotine withdrawal symptoms in humans, as they are in mice. To that end, I moved to the Human Neuroimaging Lab in Baylor. This center has state of the art imaging facilities, being the only center of its kind in the world with five scanners devoted solely to brain research. In addition, there are in Baylor several faculty members with expertise on both tobacco addiction research and in several imaging techniques. My short term goal is to use functional magnetic resonance imaging (fMRI) in human smokers and non- smokers to study brain mechanisms of tobacco withdrawal with special attention to the habenula, a small brain region that I showed that in mice, is critical for nicotine withdrawal. During the K01 award, I plan to become proficient in imaging and genetic techniques, and to collect enough data to write an R01 grant and at least 3 papers. Description of Research Project Tobacco addiction is the number one cause of preventable death in America. Recent studies have linked certain genetic variants in a subgroup of nicotinic acetylcholine receptor subunits (13, 15 and 24) to tobacco addiction risk. I will use functional magnetic resonance imaging (fMRI) to study patterns of brain activity during passive learning in non smokers and in sated and abstinent smokers. In the passive learning task, the activity of the reward system is modulated while subjects learn a cue-reward relationship. This task allows for the study of both learning and reward processing, which are compromised in abstinent smokers. The 13, 15 and 24 subunits are highly expressed in the habenula, an area which has been recently shown to be a critical part of the reward system in mammals. In addition, we have shown that the habenula is necessary for nicotine withdrawal in mice. The study of the habenula in humans has been hampered by its small size, which makes it difficult to image it in fMRI studies. We have developed a method to study habenular activity in humans during the passive learning paradigm, and we are now capable of studying habenular activity related to tobacco use and withdrawal. In addition, I will genotype a series of single nucleotide polymorphisms in all studied subjects to correlate genetic background and tobacco-dependent habenular activity. These experiments will provide a mechanism for the increased risk of tobacco addiction carried by those genetic variants. In summary, I will study brain activity during nicotine withdrawal in a genetically defined population, with special emphasis on the reward system, including the habenula and dopaminergic areas. I hope that this data will open new avenues to help design genetic background-specific drugs to treat tobacco addiction. PUBLIC HEALTH RELEVANCE: Tobacco abuse is a behavioral pattern that is very difficult to break, mainly because of withdrawal symptoms. To help design better anti-tobacco abuse therapies, we will study which parts of the brain and which genes are involved in tobacco abuse behavior and withdrawal symptoms.